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The causes of balancing selection on immunity genes: from populations to molecular interactions.

免疫基因平衡选择的原因：从群体到分子相互作用。

基本信息

批准号：
10394720
负责人：
Robert L Unckless
金额：
$ 36.39万
依托单位：
UNIVERSITY OF KANSAS LAWRENCE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-17 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10394720
关键词：
Adaptive Immune System Address Alleles Amino Acids Animals Antibiotic Resistance Antimicrobial Effect Autoimmune Binding Biological Assay Biological Models Cells Cessation of life Communicable Diseases Complement DNA Sequence Data Dissection Drosophila genus Environment Equilibrium Evolution Exhibits Gene Frequency Genes Genetic Genetic Polymorphism Genetic Variation Genotype Goals Growth Health Host Defense Human Immune Immune system Immunity In Vitro Individual Infection Innate Immune System Insecta Invertebrates Lead Life Light Link Maintenance Measures Membrane Microbe Minimum Inhibitory Concentration measurement Modeling Molecular Molecular Genetics Molecular Profiling Mutation Natural Immunity Natural Selections Organism Outcome Partner in relationship Pathway interactions Pattern Peptides Plants Play Population Predatory Behavior Process Publishing Reporting Resistance Role Secure Specificity Testing Therapeutic Time Variant Whole Organism Work antimicrobial antimicrobial peptide arms race causal variant cost cost effective economic cost experimental study fitness flexibility genetic evolution genome editing gut microbiota human disease human pathogen in vivo innovation insight laboratory experiment life history male microbiota mutant pathogen peptide drug peptide structure pressure protein function success trait

项目摘要

Project Summary Immunity is an enormously important topic for human health with economic costs of infectious disease eclipsing $100 billion in 2014. At the same time, the evolution of the immune system is fertile ground for the study of evolutionary processes because a) natural selection on immunity is intense since the outcome of infection is often life or death and b) pathogens have the ability to respond to host adaptation leading to rapid evolution through an evolutionary arms race. Since insects lack an adaptive immune system, they are excellent models to understand the molecular genetics and evolution of innate immunity. An important component of innate immunity is the complement of antimicrobial peptides (AMPs) that are produced and secreted by host cells upon infection and directly inhibit pathogens. Variation in the genes encoding these AMPs is often maintained by balancing selection, the process by which multiple alleles are maintained at the same locus through various mechanisms. While instances of balancing selection are being reported more and more frequently, we lack a comprehensive understanding of the mechanistic basis of balancing selection in most examples. The ability to connect broad scale patterns of DNA sequence diversity to mechanistic differences in protein function is innovative and would provide a comprehensive view of balancing selection. Furthermore, the identification of particular amino acid polymorphisms that are maintained by balancing selection facilitates the mechanistic study of balancing selection because the presumptive causative mutations are known a priori. Our use of Drosophila as a model system also allows for study of AMP variation in vivo in a way that is much more cost effective than several other model systems, while allowing the flexibility to move between in vitro and whole organism in vivo study. These peptides are ideal for the functional study of balancing selection because a) genetic variation in several peptides is maintained by balancing selection, providing replication, b) AMPs are effectors and thus interact directly with pathogens and c) AMPs are small and can be easily studied in vitro. Aim 1 involves determining peptide differences in vitro to understand how single amino acid changes lead to different function. Aim 2 will determine the effect of AMP variation on the entire organism and investigate the role of life history tradeoffs in balancing selection. The project is significant because it will provide a deeper understanding of evolutionary processes by uncovering molecular mechanisms and may provide a better understanding of innate immunity to enhance our treatment of human disease.

项目摘要免疫是人类健康的一个极其重要的主题，传染病的经济成本在2014年超过1000亿美元。与此同时，免疫系统的进化也是免疫系统的肥沃土壤。进化过程的研究，因为a）免疫的自然选择是激烈的，因为结果感染通常是生死攸关的，并且B）病原体具有响应宿主适应的能力，导致快速的通过进化军备竞赛来进化。由于昆虫缺乏适应性免疫系统，模型来理解先天免疫的分子遗传学和进化。的重要组成部分天然免疫是由宿主产生和分泌的抗菌肽（AMP）的补充细胞感染并直接抑制病原体。编码这些AMP的基因的变异通常是通过平衡选择来维持，通过平衡选择，多个等位基因被保持在同一基因座上的过程通过各种机制。虽然平衡选择的实例越来越多地被报道通常，我们缺乏对大多数情况下平衡选择的机制基础的全面理解。例子.将DNA序列多样性的大规模模式与基因组中的机制差异联系起来的能力，蛋白质功能是创新的，并将提供一个全面的观点平衡选择。而且通过平衡选择维持的特定氨基酸多态性的鉴定有助于平衡选择的机械研究，因为假定的致病突变是先验已知的。我们使用果蝇作为模型系统也允许以一种更复杂的方式研究体内AMP的变化。比其他几种模型系统更具成本效益，同时允许在体外和全生物体体内研究。这些肽对于平衡选择的功能研究是理想的，因为 a）通过平衡选择维持几种肽的遗传变异，提供复制，B）AMP是 c）AMP是小的并且可以容易地在体外研究。目的1涉及在体外确定肽的差异，以了解单个氨基酸的变化如何导致不同的功能。目的2将确定AMP变异对整个生物体的影响，并研究AMP变异对整个生物体的影响。生活史权衡在平衡选择中的作用。该项目意义重大，因为它将提供一个更深层次的通过揭示分子机制来理解进化过程，并可能提供更好的对先天免疫的理解，以提高我们对人类疾病的治疗。